EP2462126B1 - Method for stereoselective synthesis of bicyclic heterocycles - Google Patents

Method for stereoselective synthesis of bicyclic heterocycles Download PDF

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EP2462126B1
EP2462126B1 EP10737572.7A EP10737572A EP2462126B1 EP 2462126 B1 EP2462126 B1 EP 2462126B1 EP 10737572 A EP10737572 A EP 10737572A EP 2462126 B1 EP2462126 B1 EP 2462126B1
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formula
reaction
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Markus Ostermeier
Juergen Daeubler
Guenther Huchler
Stephan Kling
Marco Santagostino
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Boehringer Ingelheim International GmbH
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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Description

Gegenstand der vorliegenden Erfindung sind Verfahren zur stereoselektiven Herstellung von Verbindungen der Formeln (1A) und (1 B)

Figure imgb0001
Figure imgb0002
 und deren Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren und Basen, welche wertvolle pharmakologische Eigenschaften aufweisen, insbesondere eine Hemmwirkung auf die durch Tyrosinkinasen vermittelte Signaltransduktion, deren Verwendung zur Behandlung von Krankheiten, insbesondere von Tumorerkrankungen sowie der benignen Prostatahyperplasie (BPH), von Erkrankungen der Lunge und der Atemwege.The present invention relates to processes for the stereoselective preparation of compounds of the formulas (1A) and (1B)
Figure imgb0001
Figure imgb0002
 and their salts, in particular their physiologically tolerated salts with inorganic or organic acids and bases, which have valuable pharmacological properties, in particular an inhibitory effect on tyrosine kinase-mediated signal transduction, their use for the treatment of diseases, in particular tumors and benign prostatic hyperplasia (BPH) , diseases of the lungs and respiratory tract.

Hintergrund der ErfindungBackground of the invention

Chinazolinderivate sind aus dem Stand der Technik als Wirkstoffe beispielsweise zur Behandlung von Tumorerkrankungen als auch von Erkrankungen der Lunge und der Atemwege bekannt. Verfahren zur Herstellung von Chinazolinderivaten werden in WO03082831 und WO09098061 beschrieben.Quinazoline derivatives are known in the art as drugs, for example, for the treatment of tumors as well as diseases of the lung and the respiratory tract. Processes for the preparation of quinazoline derivatives are described in WO03082831 and WO09098061 described.

Es ist die Aufgabe der vorliegenden Erfindung ein stereoselektive Verfahren zur Herstellung der erfindungsgemäßen Chinazolinderivate bereitzustellen.It is the object of the present invention to provide a stereoselective process for the preparation of quinazoline derivatives of the invention.

Beschreibung der ErfindungDescription of the invention

Die vorliegende Erfindung löst die vorstehend genannte Aufgabe über das im Folgenden beschriebene Syntheseverfahren.The present invention solves the above object via the synthesis method described below.

Gegenstand der Erfindung ist somit ein Verfahren zur stereoselektiven Herstellung der Verbindung der Formel (1A)

Figure imgb0003
gegebenenfalls in Form ihrer Tautomeren, sowie gegebenenfalls ihrer pharmakologisch unbedenklichen Säureadditionssalze,
dadurch gekennzeichnet, dass das Verfahren die Reaktionsschritte (A), (B), (V), (X), (R), (S) und (T) umfasst, wobei

  • (A) die Umsetzung von 1,4-cyclohexandion-mono-ethylenketal zu einer Verbindung der Formel (1)
    Figure imgb0004
  • (B) die Umsetzung einer Verbindung der Formel (1) zu der Verbindung der Formel (2)
    Figure imgb0005
  • (V) die Umsetzung einer Verbindung der Formel (2) mit einem Schutzgruppenreagenz, vorzugsweise mit Chlorameisensäurebenzylester, zu der Verbindung der Formel (19)
    Figure imgb0006
  • (X) die Umsetzung einer Verbindung der Formel (19) zu der Verbindung der Formel (18)
    Figure imgb0007
  • (R) die Umsetzung einer Verbindung der Formel (18) mit einer Verbindung der Formel (23)
    Figure imgb0008
     zu einer Verbindung der Formel (21)
    Figure imgb0009
  • (S) die Abspaltung der Schutzgruppen, vorzugsweise des Benzylrestes und des Cbz -Restes, der Verbindung der Formel (21) zu einer Verbindung der Formel (22)
    Figure imgb0010
     und
  • (T) die Chlorierung der Verbindung der Formel (22) und anschließende Umsetzung mit 3-Chlor-2-Fluoranilin
bedeutet,
wobei die Schritte (A) bis (T) in der genannten Reihenfolge nacheinander erfolgen und
die Schutzgruppe Sg1 einen Rest ausgewählt aus der Gruppe bestehend aus gegebenenfalls substituiertes Benzyl, Cbz und gegebenenfalls substituiertes Acetyl, vorzugsweise Trifluoracetyl , insbesondere bevorzugt Cbz, sowie,
die Schutzgruppe Sg2 gegebenenfalls substituiertes Benzyl, vorzugsweise Benzyl,
bedeuten können.The invention thus provides a process for the stereoselective preparation of the compound of the formula (1A)
Figure imgb0003
 optionally in the form of their tautomers, and optionally of their pharmacologically acceptable acid addition salts,
characterized in that the method comprises the reaction steps (A), (B), (V), (X), (R), (S) and (T) , wherein
  • (A) the reaction of 1,4-cyclohexanedione monoethylene ketal to give a compound of formula (1)
    Figure imgb0004
  • (B) the reaction of a compound of formula (1) to the compound of formula (2)
    Figure imgb0005
  • (V) the reaction of a compound of the formula (2) with a protective group reagent, preferably with benzyl chloroformate, to give the compound of the formula (19)
    Figure imgb0006
  • (X) the reaction of a compound of formula (19) to the compound of formula (18)
    Figure imgb0007
  • (R) the reaction of a compound of the formula (18) with a compound of the formula (23)
    Figure imgb0008
     to a compound of formula (21)
    Figure imgb0009
  • (S) splitting off the protective groups, preferably the benzyl radical and the Cbz radical, of the compound of the formula (21) to give a compound of the formula (22)
    Figure imgb0010
     and
  • (T) the chlorination of the compound of formula (22) and subsequent reaction with 3-chloro-2-fluoroaniline
means
wherein steps (A) to (T) are sequentially performed in said order, and
the protective group Sg 1 is a radical selected from the group consisting of optionally substituted benzyl, Cbz and optionally substituted acetyl, preferably trifluoroacetyl, particularly preferably Cbz, and
the protecting group Sg 2 optionally substituted benzyl, preferably benzyl,
can mean.

Bevorzugt ist ein Verfahren zur stereoselektiven Herstellung einer Verbindung der Formel (18), dadurch gekennzeichnet, dass das Verfahren aus den Verfahrensschritten (A), (B), (V) und (X) besteht.Preferred is a process for the stereoselective preparation of a compound of formula (18), characterized in that the process consists of process steps (A), (B), (V) and (X) .

Ein weiterer Gegenstand der Erfindung ist ein Verfahren zur stereoselektiven Herstellung der Verbindung der Formel (1 B)

Figure imgb0011
gegebenenfalls in Form ihrer Tautomeren, sowie gegebenenfalls ihrer pharmakologisch unbedenklichen Säureadditionssalze,
dadurch gekennzeichnet, dass das Verfahren die Reaktionsschritte (A), (B), (Z), (H), (P), (Q), (M), (N) und (O) umfasst, wobei

  • (A) die Umsetzung von 1,4-Cyclohexandion-mono-ethylenketal zu einer Verbindung der Formel (1)
    Figure imgb0012
  • (B) die Umsetzung einer Verbindung der Formel (1) zu der Verbindung der Formel (2)
    Figure imgb0013
  • (Z) die Umsetzung einer Verbindung der Formel (2) zu der Verbindung der Formel (16)
    Figure imgb0014
  • (H) die Umsetzung einer Verbindung der Formel (16) zu der Verbindung der Formel (6)
    Figure imgb0015
  • (P) die Umsetzung einer Verbindung der Formel (6) mit einer Verbindung der Formel (23)
    Figure imgb0016
     zu einer Verbindung der Formel (7)
    Figure imgb0017
  • (Q +M) die Abspaltung der Schutzgruppen der Verbindung der Formel (7) zu einer Verbindung der Formel (12)
    Figure imgb0018
     und
  • (N + O) die Chlorierung der Verbindung der Formel (12) und anschließende Umsetzung mit 3-Chlor-2-Fluoranilin
bedeutet,
wobei die Schritte (A) bis (O) in der genannten Reihenfolge nacheinander erfolgen und
die Schutzgruppe Sg1 einen Rest ausgewählt aus der Gruppe bestehend aus gegebenenfalls substituiertes Benzyl, Cbz und gegebenenfalls substituiertes Acetyl, vorzugsweise Trifluoracetyl , insbesondere bevorzugt Cbz,
die Schutzgruppe Sg2 gegebenenfalls substituiertes Benzyl, vorzugsweise Benzyl,
bedeuten können.Another object of the invention is a process for the stereoselective preparation of the compound of formula (1 B)
Figure imgb0011
 optionally in the form of their tautomers, and optionally of their pharmacologically acceptable acid addition salts,
characterized in that the method comprises the reaction steps (A), (B), (Z), (H), (P), (Q), (M), (N) and (O) wherein
  • (A) the reaction of 1,4-cyclohexanedione monoethylene ketal to give a compound of formula (1)
    Figure imgb0012
  • (B) the reaction of a compound of formula (1) to the compound of formula (2)
    Figure imgb0013
  • (Z) the reaction of a compound of the formula (2) to give the compound of the formula (16)
    Figure imgb0014
  • (H) the reaction of a compound of formula (16) to the compound of formula (6)
    Figure imgb0015
  • (P) the reaction of a compound of the formula (6) with a compound of the formula (23)
    Figure imgb0016
     to a compound of formula (7)
    Figure imgb0017
  • (Q + M) the removal of the protective groups of the compound of the formula (7) to give a compound of the formula (12)
    Figure imgb0018
     and
  • (N + O ) the chlorination of the compound of formula (12) and subsequent reaction with 3-chloro-2-fluoroaniline
means
wherein steps (A) to (O) are sequentially performed in said order, and
the protective group Sg 1 is a radical selected from the group consisting of optionally substituted benzyl, Cbz and optionally substituted acetyl, preferably trifluoroacetyl, particularly preferably Cbz,
the protecting group Sg 2 optionally substituted benzyl, preferably benzyl,
can mean.

Ein weiterer Gegenstand der Erfindung ist ein Verfahren zur stereoselektiven Herstellung einer Verbindung der Formel (1 B), dadurch gekennzeichnet, dass in dem Verfahren die Verfahrensschritte [(Z), (H)] durch die Verfahrensschritte [(C), (D), (E) oder (F), und (G)] ersetzt werden, wobei

  • (C) die Umsetzung einer Verbindung der Formel (2) zu der Verbindung der Formel (3)
    Figure imgb0019
  • (D) die Umsetzung einer Verbindung der Formel (3) zu der Verbindung der Formel (4)
    Figure imgb0020
  • (E)oder (F) die Umsetzung einer Verbindung der Formel (4) zu der Verbindung der Formel (5)
    Figure imgb0021
     wobei in Schritt (F) die Verbindung (5) nicht isoliert wird,
    und
  • (G) die Umsetzung einer Verbindung der Formel (5) zu der Verbindung der Formel (6)
    Figure imgb0022
     bedeuten,
wobei die Schritte (C) bis (G) in der genannten Reihenfolge nacheinander erfolgen und
die Schutzgruppe Sg1 einen Rest ausgewählt aus der Gruppe bestehend aus gegebenenfalls substituiertes Benzyl, Cbz und gegebenenfalls substituiertes Acetyl, vorzugsweise Trifluoracetyl, insbesondere bevorzugt Cbz,
die Schutzgruppe Sg3 einen Rest ausgewählt aus der Gruppe bestehend aus Boc und Allyloxycarbonyl , insbesondere bevorzugt Boc,
bedeuten können.Another object of the invention is a process for the stereoselective preparation of a compound of formula (1 B), characterized in that in the process, the method steps [(Z), (H)] by the method steps [(C), (D), (E) or (F), and (G)] are replaced, wherein
  • (C) the reaction of a compound of the formula (2) into the compound of the formula (3)
    Figure imgb0019
  • (D) the reaction of a compound of formula (3) to the compound of formula (4)
    Figure imgb0020
  • (E) or (F) the reaction of a compound of the formula (4) to give the compound of the formula (5)
    Figure imgb0021
     wherein in step (F) the compound (5) is not isolated,
    and
  • (G) the reaction of a compound of formula (5) to the compound of formula (6)
    Figure imgb0022
     mean,
wherein steps (C) to (G) are sequentially performed in said order, and
the protective group Sg 1 is a radical selected from the group consisting of optionally substituted benzyl, Cbz and optionally substituted acetyl, preferably trifluoroacetyl, particularly preferably Cbz,
the protecting group Sg 3 is a radical selected from the group consisting of Boc and allyloxycarbonyl, particularly preferably Boc,
can mean.

Ein weiterer Gegenstand der Erfindung ist ein Verfahren zur stereoselektiven Herstellung einer Verbindung der Formel (1 B), dadurch gekennzeichnet, dass in dem Verfahren die Verfahrensschritte [(P), (Q), (M)] durch die Verfahrensschritte [(I), (J), (K), (L)] ersetzt werden, wobei

  • (I) die Umsetzung einer Verbindung der Formel (6) mit einer Verbindung der Formel (15)
    Figure imgb0023
     zu der Verbindung der Formel (9)
    Figure imgb0024
  • (J + K) die Abspaltung der Schutzgruppen und hydrogenolytische Reduktion einer Verbindung der Formel (9) zu der Verbindung der Formel (11)
    Figure imgb0025
     und
  • (L) die Umsetzung einer Verbindung der Formel (11) zu der Verbindung der Formel (12)
    Figure imgb0026
bedeuten,
wobei die Schritte (I) bis (L) in der genannten Reihenfolge nacheinander erfolgen und
die Schutzgruppe Sg1 einen Rest ausgewählt aus der Gruppe bestehend aus gegebenenfalls substituiertes Benzyl, Cbz und gegebenenfalls substituiertes Acetyl, vorzugsweise Trifluoracetyl , insbesondere bevorzugt Cbz,
die Schutzgruppe Sg3 einen Rest ausgewählt aus der Gruppe bestehend aus Boc und Allyloxycarbonyl , insbesondere bevorzugt Boc,
bedeuten könnenAnother object of the invention is a process for the stereoselective preparation of a compound of formula (1 B), characterized in that in the process, the method steps [(P), (Q), (M)] by the method steps [(I) , (J), (K), (L)] are replaced, wherein
  • (I) the reaction of a compound of the formula (6) with a compound of the formula (15)
    Figure imgb0023
     to the compound of formula (9)
    Figure imgb0024
  • (J + K) the deprotection and hydrogenolytic reduction of a compound of formula (9) to the compound of formula (11)
    Figure imgb0025
     and
  • (L) the reaction of a compound of formula (11) to the compound of formula (12)
    Figure imgb0026
mean,
wherein steps (I) to (L) are sequentially performed in said order, and
the protective group Sg 1 is a radical selected from the group consisting of optionally substituted benzyl, Cbz and optionally substituted acetyl, preferably trifluoroacetyl, particularly preferably Cbz,
the protecting group Sg 3 is a radical selected from the group consisting of Boc and allyloxycarbonyl, particularly preferably Boc,
can mean

Ein weiterer Gegenstand der Erfindung ist die Verbindung der Formel 22, sowie deren pharmakologisch verträglichen Salze, Hydrate, Solvate und Co-Kristalle.Another object of the invention is the compound of formula 22, and their pharmacologically acceptable salts, hydrates, solvates and co-crystals.

Ein weiterer Gegenstand der Erfindung ist die Verbindung der Formel 13, sowie deren pharmakologisch verträglichen Salze, Hydrate, Solvate und Co-Kristalle. Ein weiterer Gegenstand der Erfindung ist die Verbindung der Formel 4, sowie deren pharmakologisch verträglichen Salze, Hydrate, Solvate und Co-Kristalle. Ein weiterer Gegenstand der Erfindung ist die Verbindung der Formel 5, sowie deren pharmakologisch verträglichen Salze, Hydrate, Solvate und Co-Kristalle. Ein weiterer Gegenstand der Erfindung ist die Verbindung der Formel 6, sowie deren pharmakologisch verträglichen Hydrate, Solvate und Co-Kristalle. Ein weiterer Gegenstand der Erfindung ist die Verbindung der Formel 12, sowie deren pharmakologisch verträglichen Salze, Hydrate, Solvate und Co-Kristalle.Another object of the invention is the compound of formula 13, and their pharmacologically acceptable salts, hydrates, solvates and co-crystals. Another object of the invention is the compound of formula 4, as well as their pharmacologically acceptable salts, hydrates, solvates and co-crystals. Another object of the invention is the compound of formula 5, as well as their pharmacologically acceptable salts, hydrates, solvates and co-crystals. Another object of the invention is the compound of formula 6, as well as their pharmacologically acceptable hydrates, solvates and co-crystals. Another object of the invention is the compound of formula 12, as well as their pharmacologically acceptable salts, hydrates, solvates and co-crystals.

Unter Co-Kristallen sind im Rahmen der vorliegenden Erfindung Molekülkomplexe, die zwei oder mehr verschiedene Moleküle in demselben Kristallgitter enthalten zu verstehen ( Crystal Growth & Design, 2009, Vol. 9, No. 6, 2950-2967 ; Stahly, G. P. Cryst. Growth Des. 2007, 7, 1007-1026 ), insbesondere Co-Kristalle, die gebildet werden zwischen einem molekularen oder ionischen pharmazeutischen Wirkstoffmolekül und einem Co-Kristall-Bildner, der bei Raumtemperatur als Feststoff vorliegt ( Jones, W.; Motherwell, W. D.; Trask, A. V. MRS Bull. 2006, 341, 875-879 ; Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci. 2006, 95, 499-516 ).In the context of the present invention, co-crystals are molecular complexes which contain two or more different molecules in the same crystal lattice ( Crystal Growth & Design, 2009, Vol. 6, 2950-2967 ; Stahly, GP Cryst. Growth Des. 2007, 7, 1007-1026 ), in particular co-crystals, which are formed between a molecular or ionic pharmaceutical active substance molecule and a co-crystal-forming agent which is present as a solid at room temperature ( Jones, W .; Motherwell, WD; Trask, AV MRS Bull. 2006, 341, 875-879 ; Vishweshwar, P .; McMahon, YES; Until, YES; Zaworotko, MJJ Pharm. Sci. 2006, 95, 499-516 ).

Weiterhin Insbesondere bevorzugt ist ein Verfahren, worin ein Chlorierungsmittel ausgewählt aus der Gruppe bestehend aus, Thionylchlorid, Phosphoroxychlorid, einer N-Chlorsuccinimid/ Triphenylphosphan - Kombination, einer Tetrachlorkohlenstoff/Triphenylphosphan-Kombination,
eingesetzt wird.Also particularly preferred is a process wherein a chlorinating agent is selected from the group consisting of thionyl chloride, phosphorus oxychloride, an N-chlorosuccinimide / triphenylphosphine combination, a carbon tetrachloride / triphenylphosphine combination,
is used.

Die erfindungsgemäßen Verbindungen können in Form der Tautomere sowie in Form der freien Basen oder der entsprechenden Säureadditionssalze mit pharmakologisch unbedenklichen Säuren - wie beispielsweise Säureadditionssalze mit Halogenwasserstoffsäuren, beispielsweise Chlor- oder Bromwasserstoffsäure, anorganischen Säuren, beispielsweise Phosphorsäure oder Schwefelsäure oder organischen Säuren, wie beispielsweise Oxal-, Fumar-, Diglycol-, Toluolsulfon-, Benzoe-, Bernstein-, Malein-, Salicyl-, Äpfel- oder Methansulfonsäure, vorliegen.The compounds of the invention in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, inorganic acids, for example phosphoric acid or sulfuric acid or organic acids such as oxalic, fumaric, diglycol, toluenesulfonic, benzoic, succinic, maleic, salicylic, malic or methanesulfonic acid.

Der Einsatz folgender Lösungsmittel ausgewählt aus der jeweils aufgeführten Gruppe wird in den oben beschriebenen Verfahrenschritten bevorzugt:
In Verfahrensschritt

  • A: CH2Cl2, CHCl3, THF (Tetrahydrofuran) und Dioxan
  • B: HOAc, H2O, wässrige Lösungen folgender Lösungsmittel: EtOH, THF, iPrOH, MeOH, NMP (N-Methyl-2-pyrrolidon) und DMF (Dimethylformamid)
  • V: THF, Dioxan, NMP, Me-THFund ACN (Acetonitril)
  • X: THF/EtOH/H2O und Dioxan/MeOH/H2O
  • R: NMP, Dioxan, DMF, THF und CH2Cl2
  • S: EtOH/H2O/HCl, HOAc und MeOH/H2O/HCl
  • T: ACN und NMP
  • Z: wässrige NaOH und wässrige KOH, zusätzlich dazu EtOH, MeOH, THF
  • P: NMP, Dioxan, THF und CH2Cl2
  • Q: Dioxan, THF, NMP, CH2Cl2 und EtOH
  • M: HOAc/H2O, HCl/EtOH und HCl/MeOH
  • N: Dioxan/ACN und THF/ACN
  • O: HCl/H2O, NMP, Dioxan und THF
  • C: ACN, EtOH, MeOH, iPrOH, H2O, THF und NMP
  • D: ACN, THF und NMP
  • E: H2O, EtOH, THF und Dioxan
  • F: H2O, THF, Dioxan und EtOH
  • G: H2O/THF, THF, NMP, CH2Cl2 und Dioxan
  • I: NMP, THF, Dioxan, CH2Cl2, Toluol und DMF
  • J: Dioxan, THF, NMP, CH2Cl2 und EtOH
  • K: EtOH, MeOH, iPrOH, NMP, Dioxan und THF
  • L: nPrOH, EtOH, MeOH, NMP und ACN
The use of the following solvents selected from the group listed in each case is preferred in the process steps described above:
In process step
  • A: CH 2 Cl 2 , CHCl 3 , THF (tetrahydrofuran) and dioxane
  • B: HOAc, H 2 O, aqueous solutions of the following solvents: EtOH, THF, iPrOH, MeOH, NMP (N-methyl-2-pyrrolidone) and DMF (dimethylformamide)
  • V: THF, dioxane, NMP, Me-THF and ACN (acetonitrile)
  • X: THF / EtOH / H 2 O and dioxane / MeOH / H 2 O
  • R: NMP, dioxane, DMF, THF and CH 2 Cl 2
  • S: EtOH / H 2 O / HCl, HOAc and MeOH / H 2 O / HCl
  • T: ACN and NMP
  • Z: aqueous NaOH and aqueous KOH, in addition to EtOH, MeOH, THF
  • P: NMP, dioxane, THF and CH 2 Cl 2
  • Q: dioxane, THF, NMP, CH 2 Cl 2 and EtOH
  • M: HOAc / H 2 O, HCl / EtOH and HCl / MeOH
  • N: dioxane / ACN and THF / ACN
  • O: HCl / H 2 O, NMP, dioxane and THF
  • C: ACN, EtOH, MeOH, iPrOH, H 2 O, THF and NMP
  • D: ACN, THF and NMP
  • E: H 2 O, EtOH, THF and dioxane
  • F: H 2 O, THF, dioxane and EtOH
  • G: H 2 O / THF, THF, NMP, CH 2 Cl 2 and dioxane
  • I: NMP, THF, dioxane, CH 2 Cl 2 , toluene and DMF
  • J: dioxane, THF, NMP, CH 2 Cl 2 and EtOH
  • K: EtOH, MeOH, iPrOH, NMP, dioxane and THF
  • L: nPrOH, EtOH, MeOH, NMP and ACN

Die oben beschriebenen Verfahrensschritte werden vorzugsweise in folgenden Temperaturbereichen durchgeführt:The method steps described above are preferably carried out in the following temperature ranges:

In Verfahrensschritt:

  • A: vorzugsweise -15 bis 40 °C, besonders bevorzugt -10 bis 10 °C,
  • B: vorzugsweise 20 bis 75 °C, besonders bevorzugt 35 bis 55 °C,
  • V: vorzugsweise 0 bis 50 °C, besonders bevorzugt 10 bis 35 °C,
  • X: vorzugsweise 0 bis 60 °C, besonders bevorzugt 5 bis 35 °C,
  • R: vorzugsweise 5 bis 100 °C, besonders bevorzugt 15 bis 40 °C,
  • S: vorzugsweise 50 bis 80 °C, besonders bevorzugt 65 bis 80 °C,
  • T: vorzugsweise 10 bis 80 °C, besonders bevorzugt 15 bis 50 °C,
  • Z: vorzugsweise 0 bis 60 °C, besonders bevorzugt 10 bis 35 °C,
  • H: vorzugsweise 15 bis 60 °C, besonders bevorzugt 15 bis 30 °C,
  • P: vorzugsweise 10 bis 80 °C, besonders bevorzugt 15 bis 35 °C,
  • Q: vorzugsweise 0 bis 80 °C, besonders bevorzugt 50 bis 70 °C,
  • M: vorzugsweise 20 bis 90 °C, besonders bevorzugt 60 bis 80 °C,
  • N: vorzugsweise 15 bis 85 °C, besonders bevorzugt 70 bis 85 °C,
  • O: vorzugsweise 0 bis 80 °C, besonders bevorzugt 10 bis 50 °C,
  • C: vorzugsweise 0 bis 65 °C, besonders bevorzugt 15 bis 30 °C,
  • D: vorzugsweise 10 bis 80 °C, besonders bevorzugt 20 bis 40 °C,
  • E: vorzugsweise 0 bis 40 °C, besonders bevorzugt 0 bis 15 °C,
  • F: vorzugsweise 0 bis 45 °C, besonders bevorzugt 10 bis 25 °C,
  • G: vorzugsweise 0 bis 45 °C, besonders bevorzugt 10 bis 25 °C,
  • I: vorzugsweise 0 bis 50 °C, besonders bevorzugt 15 bis 30 °C,
  • J: vorzugsweise 0 bis 85°C, besonders bevorzugt 40 bis 70 °C,
  • K: vorzugsweise 10 bis 60 °C, besonders bevorzugt 15 bis 35 °C, und
  • L: vorzugsweise 60 bis 97 °C, besonders bevorzugt 85 bis 97 °C,
In process step:
  • A: preferably -15 to 40 ° C, more preferably -10 to 10 ° C,
  • B: preferably 20 to 75 ° C, particularly preferably 35 to 55 ° C,
  • V: preferably 0 to 50 ° C, particularly preferably 10 to 35 ° C,
  • X: preferably 0 to 60 ° C, particularly preferably 5 to 35 ° C,
  • R: preferably 5 to 100 ° C, particularly preferably 15 to 40 ° C,
  • S: preferably 50 to 80 ° C, particularly preferably 65 to 80 ° C,
  • T: preferably 10 to 80 ° C, particularly preferably 15 to 50 ° C,
  • Z: preferably 0 to 60 ° C, particularly preferably 10 to 35 ° C,
  • H: preferably 15 to 60 ° C, particularly preferably 15 to 30 ° C,
  • P: preferably 10 to 80 ° C, particularly preferably 15 to 35 ° C,
  • Q: preferably 0 to 80 ° C, particularly preferably 50 to 70 ° C,
  • M: preferably 20 to 90 ° C, particularly preferably 60 to 80 ° C,
  • N: preferably 15 to 85 ° C, particularly preferably 70 to 85 ° C,
  • O: preferably 0 to 80 ° C, particularly preferably 10 to 50 ° C,
  • C: preferably 0 to 65 ° C, particularly preferably 15 to 30 ° C,
  • D: preferably 10 to 80 ° C, particularly preferably 20 to 40 ° C,
  • E: preferably 0 to 40 ° C, particularly preferably 0 to 15 ° C,
  • F: preferably 0 to 45 ° C, particularly preferably 10 to 25 ° C,
  • G: preferably 0 to 45 ° C, particularly preferably 10 to 25 ° C,
  • I: preferably 0 to 50 ° C, particularly preferably 15 to 30 ° C,
  • J: preferably 0 to 85 ° C, particularly preferably 40 to 70 ° C,
  • K: preferably 10 to 60 ° C, particularly preferably 15 to 35 ° C, and
  • L: preferably 60 to 97 ° C, particularly preferably 85 to 97 ° C,

In Verfahrensschritten K, M und S werden vorzugsweise Katalysatoren ausgewählt aus der Gruppe bestehend aus Pd/C, Pd(OH)2 bevorzugt Pd/C, eingesetzt.In process steps K, M and S, preference is given to using catalysts selected from the group consisting of Pd / C, Pd (OH) 2, preferably Pd / C.

Es werden vorzugsweise Schutzgruppen ausgewählt aus der Gruppe bestehend aus Benzyl, Cbz, Trifluoracetyl und Boc eingesetzt.It is preferred to use protecting groups selected from the group consisting of benzyl, Cbz, trifluoroacetyl and Boc.

Die in obigen Formeln verwendete Abkürzung Boc bedeutet teriär butyl carbamat und Cbz bedeutet Benzyloxycarbonyl.The abbreviation Boc used in the above formulas means teriary butyl carbamate and Cbz means benzyloxycarbonyl.

Unter dem Begriff "gegebenenfalls substituiertes Benzyl" sind beispielsweise Reste ausgewählt aus der Gruppe bestehend aus Benzyl, para-Methoxybenzyl, para-Methylbenzyl und 1-Phenylethyl, insbesondere bevorzugt Benzyl, zu verstehen. Unter dem Begriff "gegebenenfalls substituiertes Acetyl" sind beispielsweise Reste ausgewählt aus der Gruppe bestehend aus Trifluoracetyl, Acetyl, Monofluoracetyl, Difluoracetyl und Trichloracetyl, insbesondere bevorzugt Trifluoracetyl, zu verstehen.The term "optionally substituted benzyl" is to be understood as meaning, for example, radicals selected from the group consisting of benzyl, para-methoxybenzyl, para-methylbenzyl and 1-phenylethyl, particularly preferably benzyl. The term "optionally substituted acetyl" is understood as meaning, for example, radicals selected from the group consisting of trifluoroacetyl, acetyl, monofluoroacetyl, difluoroacetyl and trichloroacetyl, in particular preferably trifluoroacetyl.

Schema 1 und 2 illustrieren die erfindungsgemäße Synthese. Sämtliche Verbindungen sind in Form ihrer Basen dargestellt.

Figure imgb0027
Figure imgb0028
 Schemes 1 and 2 illustrate the synthesis of the invention. All compounds are shown in the form of their bases.
Figure imgb0027
Figure imgb0028

Die nachfolgenden Beispiele dienen der Illustration der exemplarisch durchgeführten Verfahren zur Herstellung der Verbindungen der Formen (1A) und (1 B). Diese Beispiele sind als Erläuterung der Erfindung zu verstehen, ohne selbiges auf deren Gegenstand zu beschränken.The following examples serve to illustrate the exemplified procedures for preparing the compounds of the forms (1A) and (1B). These examples are to be understood as an explanation of the invention without limiting the same to their subject matter.

Beispiel 1example 1 1, 4-Dioxa-9,12-diaza-dispiro[4.2.5.2]pentadecan-13-one1,4-dioxa-9,12-diaza-dispiro [4.2.5.2] pentadecane-13-one

Figure imgb0029
Figure imgb0029

Verfahrensschritt AProcess step A

Zu einer auf -5°C abgekühlten Mischung aus 250 g 1,4-cyclohexandion-mono-ethylenketal, 18.2 g Benzyltriethylammoniumchlorid, 1.57 g Natriumcyanid in 1 I Dichlormethan werden 127.5 ml Ethylendiamin in 194 ml Chloroform zugetropft. Anschließend werden bei ca. -10 bis 0°C 407.5 ml 50%ige Natronlauge innerhalb der nächsten 9 h zugetropft. Nach 14.5 h bei -5 bis 25°C werden 500 ml konz. Salzsäure zugetropft. Der Niederschlag wird abfiltriert und zweimal mit je 500 ml Dichlormethan gewaschen. Das Filtrat wird phasengetrennt. Die wässrige Phase wird zweimal mit je 1 l Dichlormethan und einmal mit 500 ml Dichlormethan extrahiert. Die vereinigten organischen Phasen werden über Natriumsulfat getrocknet und im Vakuum eingeengt. Es werden 500 ml n-Butylacetat zugegeben und weiter soweit eingeengt, dass 820g Suspension übrig bleiben. Bei 50°C werden innerhalb von 20 min 3 I Methyl-tert-butylether zugegeben. Der Niederschlag wird abgesaugt und zweimal mit je 200 ml Methyl-tert-butylether gewaschen. Nach Trocknen erhält man 247 g Produkt.
Massenspektrum (ESI+): m/z = 227 [M+H]+ To a cooled to -5 ° C mixture of 250 g of 1,4-cyclohexanedione mono-ethylene ketal, 18.2 g Benzyltriethylammoniumchlorid, 1.57 g of sodium cyanide in 1 l of dichloromethane are added dropwise 127.5 ml of ethylenediamine in 194 ml of chloroform. Then 407.5 ml of 50% sodium hydroxide solution are added dropwise at about -10 to 0 ° C within the next 9 h. After 14.5 h at -5 to 25 ° C 500 ml of conc. Hydrochloric acid added dropwise. The precipitate is filtered off and washed twice with 500 ml of dichloromethane. The filtrate is phase separated. The aqueous phase is extracted twice with 1 l of dichloromethane and once with 500 ml of dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. 500 ml of n-butyl acetate are added and the mixture is concentrated to the extent that 820 g suspension remain. At 50 ° C 3 l of methyl tert-butyl ether are added within 20 min. The precipitate is filtered off with suction and washed twice with 200 ml of methyl tert-butyl ether. After drying, 247 g of product are obtained.
Mass spectrum (ESI + ): m / z = 227 [M + H] +

Beispiel 2Example 2 1,4-Diaza-spiro[5.5]undecane-5,9-dione1,4-diaza-spiro [5.5] undecane-5,9-dione

Figure imgb0030
Figure imgb0030

Verfahrensschritt BProcess step B

Zu 500 g 1,4-Dioxa-9,12-diaza-dispiro[4.2.5.2]pentadecan-13-one in 2.5 l Essigsäure werden 310 ml 10M HCl in Ethanol innerhalb von 45 min zugetropft. Nach 3 h bei 35-45°C werden innerhalb von 20 min 10 l Isopropanol zugetropft. Die Suspension wird auf 15°C abgekühlt und filtriert. Der Niederschlag wird zweimal mit je 1 l Isopropanol und zweimal mit je 1 I Methyl-tert-butylether gewaschen. Nach Trocknen des Feststoffs erhält man 386 g Produkt als Hydrochlorid.
Massenspektrum (ESI+): m/z = 183 [M+H]+ To 500 g of 1,4-dioxa-9,12-diaza-dispiro [4.2.5.2] pentadecane-13-one in 2.5 l of acetic acid, 310 ml of 10M HCl in ethanol are added dropwise within 45 min. After 3 h at 35-45 ° C, 10 l of isopropanol are added dropwise within 20 min. The suspension is cooled to 15 ° C and filtered. The precipitate is washed twice with 1 l of isopropanol and twice with 1 l of methyl tert-butyl ether. After drying the solid, 386 g of product are obtained as the hydrochloride.
Mass spectrum (ESI + ): m / z = 183 [M + H] +

Verfahrensschritt CProcess step C

380 g 1,4-Diaza-spiro[5.5]undecane-5,9-dione hydrochoride in 3.8 l Acetonitril werden innerhalb einer Stunde mit 320 ml 30%iger Natriummethylat-Lösung in Methanol versetzt. 18 g Natriumcarbonat werden zugegeben und der Ansatz für 18 h gerührt. Es werden 2 l Lösungsmittel abdestilliert und der Rückstand filtriert. Der Filterkuchen wird zweimal mit je 100 ml Acetonitril gewaschen und das Filtrat, welches das Produkt enthält, wird direkt in der nächsten Stufe weiter umgesetzt.380 g of 1,4-diaza-spiro [5.5] undecane-5,9-dione hydrochoride in 3.8 l of acetonitrile are mixed within one hour with 320 ml of 30% sodium methylate solution in methanol. 18 g of sodium carbonate are added and the batch is stirred for 18 h. 2 l of solvent are distilled off and the residue is filtered. The filter cake is washed twice with 100 ml each of acetonitrile and the filtrate containing the product is reacted further directly in the next step.

Beispiel 3Example 3 5,9-Dioxo-1,4-diaza-spiro[5.5]undecane-4-carboxylic acid tert-butyl ester5,9-Dioxo-1,4-diaza-spiro [5,5] undecane-4-carboxylic acid tert-butyl ester

Figure imgb0031
Figure imgb0031

Verfahrensschritt DProcess step D

Zu der Lösung aus dem vorherigen Ansatz, die das 1,4-Diaza-spiro[5.5]undecane-5,9-dione enthält, werden 480 g Kaliumcarbonat und 10 g 4-(Dimethylamino)-pyridin zugefügt. 415 g Di-tert-butyldicarbonat in 415 ml Acetonitril werden innerhalb von 200 min zugetropft. Nach 18.5 h werden 10 g 4-(Dimethylamino)-pyridin und 100 g Di-tert-butyldicarbonat in 100 ml Acetonitril zugegeben. Nach 200 min werden 100 g Di-tert-butyldicarbonat in 100 ml Acetonitril zugegeben. Nach 90 min werden 50 g Ditert-butyldicarbonat in 50 ml Acetonitril zugegeben. Nach 1 h werden 2 l Wasser zugegeben. Nach Phasentrennung wird die wässrige Phase mit 1 I Methyl-tert-butylether gewaschen. Die vereinigten organischen Phasen werden mit 1 l 10%iger Kaliumcarbonatlösung und 500 ml ges. Kochsalzlösung gewaschen. Die organische Phase wird im Vakuum eingeengt. Zur Suspension werden 1.5 l n-Butylacetat zugegeben und es wird erneut eingeengt. Es werden nochmals 2 I n-Butylacetat zugegeben und erneut eingeengt. Die zurückbleibende Suspension wird auf 55°C erwärmt und langsam mit 1 I Methyl-tert-butylether versetzt. Die Suspension wird auf 22°C abgekühlt. Der Niederschlag wird abfiltriert und mit 500 ml n-Butylacetat und 500 ml Methyl-tert-butylether gewaschen. Nach Trocknen des Feststoffs erhält man 296 g des Produkts.
Massenspektrum (ESI+): m/z = 283 [M+H]+ To the solution from the previous batch containing the 1,4-diaza-spiro [5.5] undecane-5,9-dione, 480 g of potassium carbonate and 10 g of 4- (dimethylamino) -pyridine are added. 415 g of di-tert-butyl dicarbonate in 415 ml of acetonitrile are added dropwise within 200 min. After 18.5 hours, 10 g of 4- (dimethylamino) -pyridine and 100 g of di-tert-butyl dicarbonate in 100 ml of acetonitrile are added. After 200 minutes, 100 g of di-tert-butyl dicarbonate in 100 ml of acetonitrile are added. After 90 minutes, 50 g of di-tert-butyldicarbonate in 50 ml of acetonitrile are added. After 1 h, 2 l of water are added. After phase separation, the aqueous phase is washed with 1 l of methyl tert-butyl ether. The combined organic phases are washed with 1 l of 10% potassium carbonate solution and 500 ml of sat. Washed saline. The organic phase is concentrated in vacuo. To the suspension 1.5 l of n-butyl acetate are added and it is concentrated again. There are added again 2 I n-butyl acetate and concentrated again. The remaining suspension is heated to 55 ° C and slowly treated with 1 l of methyl tert-butyl ether. The suspension is cooled to 22 ° C. The precipitate is filtered off and washed with 500 ml of n-butyl acetate and 500 ml of methyl tert-butyl ether. After drying the solid gives 296 g of the product.
Mass Spectrum (ESI + ): m / z = 283 [M + H] +

Beispiel 4Example 4 (cis)-9-Hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecane-4-carboxylic acid tert-butyl ester(cis) -9-Hydroxy-5-oxo-1,4-diaza-spiro [5,5] undecane-4-carboxylic acid tert-butyl ester

Figure imgb0032
Figure imgb0032

Verfahrensschritt EProcess step E

Zu einer Mischung aus 159 g 5,9-Dioxo-1,4-diaza-spiro[5.5]undecane-4-carboxylic acid tert-butyl ester in 1140 ml Wasser werden bei 1°C innerhalb von 17 min 6.4 g Natriumborhydrid in 100 ml Wasser zugetropft. Der Tropftrichter wird mit 30 ml Wasser nachgespült. Nach 50 min werden 318 ml ges. Kaliumcarbonatlösung zugegeben und nach Rühren für 1 h bei 10°C wird der Niederschlag abgesaugt und zweimal mit je 200 ml 10%iger Kaliumcarbonatlösung gewaschen. Nach Trocknen wird der Niederschlag in 1.6 I Wasser für 4.5 h gerührt. Es werden 350 ml ges. Kaliumcarbonatlösung zugegeben und nach Rühren für 15 min wird der Niederschlag abgesaugt und mit 200 ml 10%iger Kaliumcarbonatlösung gewaschen. Nach Trocknen wird der Niederschlag in 500 ml Tetrahydrofuran für 20 min gerührt. Nach Filtration, Nachwaschen mit 200 ml Tetrahydrofuran und Eindampfen des Filtrats erhält man 65.5 g Produkt.
Massenspektrum (ESI+): m/z = 285 [M+H]+ To a mixture of 159 g of 5,9-dioxo-1,4-diaza-spiro [5.5] undecane-4-carboxylic acid tert-butyl ester in 1140 ml of water at 1 ° C within 17 min 6.4 g of sodium borohydride in 100 ml of water added dropwise. The dropping funnel is rinsed with 30 ml of water. After 50 minutes, 318 ml of sat. Potassium carbonate solution is added and after stirring for 1 h at 10 ° C, the precipitate is filtered off with suction and washed twice with 200 ml of 10% potassium carbonate solution. After drying, the precipitate is stirred in 1.6 L of water for 4.5 h. There are 350 ml sat. Potassium carbonate solution was added and after stirring for 15 min, the precipitate is filtered off with suction and washed with 200 ml of 10% potassium carbonate solution. After drying, the precipitate is stirred in 500 ml of tetrahydrofuran for 20 min. After filtration, washing with 200 ml of tetrahydrofuran and evaporation of the filtrate gives 65.5 g of product.
Mass spectrum (ESI + ): m / z = 285 [M + H] +

Verfahrensschritt FProcess step F

Zu einer Lösung aus 113 g 5,9-Dioxo-1,4-diaza-spiro[5.5]undecane-4-carboxylic acid tert-butyl ester in 1150 ml THF und 25 ml Wasser werden bei 16°C innerhalb von 20 min 3.8 g Natriumborhydrid in 30 ml Wasser zugetropft. Nach 45 min werden 0.42 g Natriumborhydrid zugegeben. Nach 35 min werden 0.42 g Natriumborhydrid zugegeben. Nach weiteren 35 min werden 0.1 g Natriumborhydrid zugegeben. Nach 15 min werden 10 ml Aceton zugefügt und das Reaktionsgemisch wird mit zweimal mit je 500 ml ges. Kochsalzlösung gewaschen. Die organische Phase wird direkt im nächsten Versuch weiterverwendet.
Massenspektrum (ESI+): m/z = 285 [M+H]+ To a solution of 113 g of 5,9-dioxo-1,4-diaza-spiro [5.5] undecane-4-carboxylic acid tert-butyl ester in 1150 ml of THF and 25 ml of water at 16 ° C within 20 min 3.8 Sodium borohydride in 30 ml of water was added dropwise. After 45 minutes, 0.42 g of sodium borohydride are added. After 35 minutes, 0.42 g of sodium borohydride are added. After a further 35 minutes, 0.1 g of sodium borohydride are added. After 15 minutes, 10 ml of acetone are added and the reaction mixture is washed twice with 500 ml each. Washed saline. The organic phase is used directly in the next experiment.
Mass spectrum (ESI + ): m / z = 285 [M + H] +

Beispiel 5Example 5 (cis)-9-Hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecane-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester(cis) -9-Hydroxy-5-oxo-1,4-diaza-spiro [5,5] undecane-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester

Figure imgb0033
Figure imgb0033

Verfahrensschritt GProcess step G

Zur Organischen Phase aus dem vorherigen Ansatz werden 112 ml ges. Kaliumcarbonatlösung zugegeben und anschließend werden 59 ml Chlorameisensäurebenzylester innerhalb von 20 min zugetropft. Nach 16 h werden 400 ml Wasser zugegeben und die Phasen getrennt. Die organische Phase wird mit 900 ml ges. Kaliumcarbonatlösung und zweimal mit je 450 ml ges. Kochsalzlösung gewaschen. Die organische Phase wird über Magnesiumsulfat getrocknet und anschließend eingeengt. Nachdem 1 l abdestilliert wurde werden 450 ml Methylcyclohexan zugegeben und weiter eingeengt. Es werden noch zweimal je 100 ml Methylcyclohexan zugegeben und weiter eingeengt, bis 168 Rohprodukt übrig bleiben. Das Rohprodukt wird dreimal aus Methanol/Wasser 1:1 umkristallisiert. Nach Trocknen erhält man 86 g Produkt.
Massenspektrum (ESI+): m/z = 419 [M+H]+ To the organic phase from the previous batch, 112 ml sat. Potassium carbonate solution is added and then 59 ml of benzyl chloroformate are added dropwise within 20 min. After 16 h, 400 ml of water are added and the phases are separated. The organic phase is saturated with 900 ml. Potassium carbonate solution and twice with 450 ml of sat. Washed saline. The organic phase is dried over magnesium sulfate and then concentrated. After 1 l has been distilled off, 450 ml of methylcyclohexane are added and the mixture is concentrated further. There are added twice more per 100 ml of methylcyclohexane and further concentrated until 168 crude product left. The crude product is recrystallized three times from methanol / water 1: 1. After drying, 86 g of product are obtained.
Mass spectrum (ESI + ): m / z = 419 [M + H] +

Verfahrensschritt H : Process step H :

Eine Mischung aus 500 mg (cis)-9-Hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecane-1-carboxylic acid benzyl ester, 217 mg Kaliumcarbonat, 686 mg Di-tert-butyldicarbonat und 192 mg 4-(Dimethylamino)-pyridin in 10 ml Acetonitril werden für 4 h bei RT gerührt. Das Gemisch wird durch zweimalige Chromatographie an Kieselgel aufgereinigt und man erhält 420 mg Produkt.
Massenspektrum (ESI+): m/z = 419 [M+H]+ A mixture of 500 mg of (cis) -9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane-1-carboxylic acid benzyl ester, 217 mg of potassium carbonate, 686 mg of di-tert-butyl dicarbonate and 192 mg 4- (Dimethylamino) -pyridine in 10 ml of acetonitrile are stirred for 4 h at RT. The mixture is purified by double chromatography on silica gel, giving 420 mg of product.
Mass spectrum (ESI + ): m / z = 419 [M + H] +

Beispiel 6Example 6 5-Hydroxy-4-methoxy-2-nitro-benzoesäuremethylester5-hydroxyl-4-methoxy-2-nitro-benzoic acid methyl ester

Figure imgb0034
Figure imgb0034

Eine Mischung aus 500 g 4,5-Dimethoxy-2-nitro-benzoesäuremethylester und 625 g Kaliumhydroxid in 2300 ml Wasser wird für 18.5 h auf 95 °C erhitzt. Nach Abkühlen wird klarfiltriert und das Filtrat mit 3 l Wasser verdünnt. Die Lösung wird mit 950 ml Essigsäure versetzt und nach 1 h wird der Niederschlag abfiltriert. Der Niederschlag wird in 3250 ml Ethylacetat suspendiert und anschließend werden 100 ml Wasser und 200 ml 12N Salzsäure zugegeben. Nach 1.5h werden die Phasen getrennt und die wässrige Phase wird mit 700 ml Ethylacetat extrahiert. Die vereinigten organischen Phasen werden über Magnesiumsulfat getrocknet und nach Filtration eingedampft. Es wird mit 200 ml Methylcyclohexan nachgedampft. Der Rückstand wird zusammen mit 1600 ml Methanol und 100 ml konz. Schwefelsäure für 16.5 h zum Rückfluss erhitzt. Der Ansatz wird eingeengt, bis die Kristallisation einsetzt. Es werden 1000 ml Wasser zugegeben und gerührt, bis eine homogene Suspension entstanden ist. Der Niederschlag wird abfiltriert, mit 500 ml Wasser gewaschen und in 1000 ml Wasser suspendiert. Nach 1.5 h Rühren wird der Niederschlag abfiltriert und mit 500 ml Wasser gewaschen. Nach Trocknen des Filterkuchens erhält man 364 g Produkt.
Massenspektrum (ESI-): m/z = 226 [M-H]+ A mixture of 500 g of 4,5-dimethoxy-2-nitro-benzoic acid methyl ester and 625 g of potassium hydroxide in 2300 ml of water is heated to 95 ° C for 18.5 h. After cooling, it is clarified by filtration and the filtrate is diluted with 3 l of water. The solution is treated with 950 ml of acetic acid and after 1 h, the precipitate is filtered off. The precipitate is suspended in 3250 ml of ethyl acetate and then 100 ml of water and 200 ml of 12N hydrochloric acid are added. After 1.5 h, the phases are separated and the aqueous phase is extracted with 700 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and evaporated after filtration. It is post-evaporated with 200 ml of methylcyclohexane. The residue is combined with 1600 ml of methanol and 100 ml of conc. Sulfuric acid heated to reflux for 16.5 h. The batch is concentrated until crystallization begins. 1000 ml of water are added and stirred until a homogeneous suspension has formed. The precipitate is filtered off, washed with 500 ml of water and suspended in 1000 ml of water. After stirring for 1.5 h, the precipitate is filtered off and washed with 500 ml of water. After drying the filter cake, 364 g of product are obtained.
Mass spectrum (ESI - ): m / z = 226 [MH] +

Beispiel 7Example 7 (trans)-9-(2-Methoxy-5-methoxycarbonyl-4-nitro-phenoxy)-5-oxo-1,4-diaza-spiro[5.5]undecane-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester(trans) -9- (2-Methoxy-5-methoxycarbonyl-4-nitro-phenoxy) -5-oxo-1,4-diaza-spiro [5.5] undecane-1,4-dicarboxylic acid 1-benzyl ester 4- tert-butyl ester

Figure imgb0035
Figure imgb0035

Verfahrensschritt IProcess step I

Zu einer Mischung aus 99 g (cis)-9-Hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecane-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester, 53.74 g 5-Hydroxy-4-methoxy-2-nitro-benzoic acid methyl ester (15) und 74.34 g Triphenylphosphin in 764 ml Dioxan werden bei RT 58.75 ml Azo-dicarbonsäure-diisopropylester innerhalb einer Stunde zugetropft. Nach 17 h werden 5 ml Azo-dicarbonsäure-diisopropylester zugegeben und der Ansatz für weitere 1.5 h gerührt. Die Mischung, die das Produkt enthält, wird ohne Aufreinigung direkt in der nächsten Stufe weiter umgesetzt.
Massenspektrum (ESI+): m/z = 645 [M+NH4]+ To a mixture of 99 g (cis) -9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester, 53.74 g 5 -Hydroxy-4-methoxy-2-nitro-benzoic acid methyl ester (15) and 74.34 g of triphenylphosphine in 764 ml of dioxane are added dropwise at RT 58.75 ml of diisopropyl azo-dicarboxylate within one hour. After 17 h, 5 ml of diisopropyl azo-dicarboxylate are added and the mixture is stirred for a further 1.5 h. The mixture containing the product is reacted further without purification directly in the next step.
Mass spectrum (ESI + ): m / z = 645 [M + NH4] +

Beispiel 8Example 8 (trans)-9-(2-Methoxy-5-methoxycarbonyl-4-nitro-phenoxy)-5-oxo-1,4-diazaspiro[5.5]undecane-1-carboxylic acid benzyl ester(trans) -9- (2-Methoxy-5-methoxycarbonyl-4-nitro-phenoxy) -5-oxo-1,4-diazaspiro [5.5] undecane-1-carboxylic acid benzyl ester

Figure imgb0036
Figure imgb0036

Verfahrensschritt JProcess step J

Zum vorherigen Ansatz, der den (trans)-9-(2-Methoxy-5-methoxycarbonyl-4-nitro-phenoxy)-5-oxo-1,4-diaza-spiro[5.5]undecane-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester enthält, werden 130 ml 4M HCl in Dioxan gegeben. Das Reaktionsgemisch wird auf 60°C erhitzt. Nach 2 h werden weitere 13 ml 4M HCl in Dioxan zugegeben. Die Reaktionslösung wird auf RT abgekühlt und mit 500 ml ges. Kaliumcarbonatlösung versetzt. Die organische Phase wird mit 500 ml ges. Kaliumcarbonat und 200 ml ges. Kochsalzlösung gewaschen. Die organische Phase, die das Produkt enthält, wird ohne Aufreinigung direkt in der nächsten Stufe weiter umgesetzt.
Massenspektrum (ESI+): m/z = 528 [M+H]+ To the previous approach, the (trans) -9- (2-methoxy-5-methoxycarbonyl-4-nitro-phenoxy) -5-oxo-1,4-diaza-spiro [5.5] undecane-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester, 130 ml of 4M HCl are added in dioxane. The reaction mixture is heated to 60.degree. After 2 hours, another 13 ml of 4M HCl in dioxane are added. The reaction solution is cooled to RT and saturated with 500 ml. Added potassium carbonate solution. The organic phase is saturated with 500 ml. Potassium carbonate and 200 ml sat. Washed saline. The organic phase containing the product is reacted further without purification directly in the next stage.
Mass spectrum (ESI + ): m / z = 528 [M + H] +

Beispiel 9Example 9 (trans)-2-Amino-4-methoxy-5-(5-oxo-1,4-diaza-spiro[5.5]undec-9-yloxy)-benzoic acid methyl ester(trans) -2-amino-4-methoxy-5- (5-oxo-1,4-diaza-spiro [5.5] undec-9-yloxy) -benzoic acid methyl ester

Figure imgb0037
Figure imgb0037

Verfahrensschritt KProcess step K

Zum vorherigen Ansatz, der den (trans)-9-(2-Methoxy-5-methoxycarbonyl-4-nitro-phenoxy)-5-oxo-1,4-diazaspiro[5.5]undecane-1-carboxylic acid benzyl ester enthält, werden 12.4 g Pd (10%) auf Kohle und 500 ml Methanol zugefügt. Nach Hydrieren mit Wasserstoff für 1.5 h bei 3 bar wird der Ansatz bis auf 600 ml Restvolumen eingeengt. Der Ansatz wird mit 1.8 l Dioxan verdünnt und klarfiltriert. 59ml 4M HCl in Dioxan werden innerhalb von 45 min zugetropft und nach weiteren 30 min wird der Niederschlag abgesaugt und zweimal mit je 200 ml Dioxan gewaschen. Nach Trocknen des Feststoffs erhält man 98.6 g des Produkts als Hydrochlorid. Massenspektrum (ESI+): m/z = 364 [M+H]+ To the previous batch containing the (trans) -9- (2-methoxy-5-methoxycarbonyl-4-nitro-phenoxy) -5-oxo-1,4-diazaspiro [5.5] undecane-1-carboxylic acid benzyl ester, 12.4 g of Pd (10%) are added on carbon and 500 ml of methanol. After hydrogenation with hydrogen for 1.5 h at 3 bar, the mixture is concentrated to 600 ml residual volume. The mixture is diluted with 1.8 l of dioxane and clarified by filtration. 59 ml of 4M HCl in dioxane are added dropwise within 45 min and after a further 30 min, the precipitate is filtered off with suction and washed twice with 200 ml of dioxane. After drying the solid, 98.6 g of the product are obtained as the hydrochloride. Mass spectrum (ESI + ): m / z = 364 [M + H] +

Beispiel 10Example 10 (trans)-9-(4-Hydroxy-7-methoxy-quinazolin-6-yloxy)-1,4-diaza-spiro[5.5]undecan-5-one(Trans) -9- (4-hydroxy-7-methoxy-quinazolin-6-yloxy) -1,4-diaza-spiro [5.5] undecane-5-one

Figure imgb0038
Figure imgb0038

Verfahrensschritt LProcess step L

88 g (trans)-2-Amino-4-methoxy-5-(5-oxo-1,4-diaza-spiro[5.5]undec-9-yloxy)-benzoic acid methyl ester hydrochloride und 25 g Formamidinacetat in 1.8 L n-Propanol werden für 17h zum Rückfluss erhitzt. Anschließend wird auf 28°C abgekühlt und 4 h bei dieser Temperatur gerührt. Nach Abkühlen auf 14°C wird der Niederschlag abfiltriert und mit 200 ml kaltem n-Propanol gewaschen. Nach Trocknen des Feststoffs erhält man 44 g des Produkts als Hydrochlorid.
Massenspektrum (ESI+): m/z = 359 [M+H]+ 88 g of (trans) -2-amino-4-methoxy-5- (5-oxo-1,4-diaza-spiro [5.5] undec-9-yloxy) -benzoic acid methyl ester hydrochloride and 25 g of formamidine acetate in 1.8 l n-Propanol is heated to reflux for 17 h. It is then cooled to 28 ° C and stirred for 4 h at this temperature. After cooling to 14 ° C, the precipitate is filtered off and washed with 200 ml of cold n-propanol. After drying the solid, 44 g of the product are obtained as the hydrochloride.
Mass spectrum (ESI + ): m / z = 359 [M + H] +

Verfahrensschritt MProcess step M

Zu einer Mischung aus 1.7 g (trans)-9-(3-Benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy)-5-oxo-1,4-diaza-spiro[5.5]undecane-1-carboxylic acid benzyl ester in 30 ml Essigsäure und 3 ml Wasser werden 300 mg Palladium (10%) auf Kohle zugefügt. Nach 22 h Hydrieren bei 70°C wird filtriert und die Lösung zur Trockne eingedampft, wobei 1.3g Produkt anfallen.
Massenspektrum (ESI+): m/z = 359 [M+H]+ To a mixture of 1.7 g of (trans) -9- (3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy) -5-oxo-1,4-diaza-spiro [ 5.5] undecane-1-carboxylic acid benzyl ester in 30 ml of acetic acid and 3 ml of water is added 300 mg of palladium (10%) on carbon. After hydrogenation at 70 ° C. for 22 h, it is filtered and the solution is evaporated to dryness, giving 1.3 g of product.
Mass spectrum (ESI + ): m / z = 359 [M + H] +

Beispiel 11Example 11 (trans)-9-(4-Chloro-7-methoxy-quinazolin-6-yloxy)-1,4-diaza-spiro[5.5]undecan-5-one(Trans) -9- (4-chloro-7-methoxy-quinazolin-6-yloxy) -1,4-diaza-spiro [5.5] undecane-5-one

Figure imgb0039
Figure imgb0039

Verfahrensschritt NProcess step N

10 g (trans)-9-(4-Hydroxy-7-methoxy-quinazolin-6-yloxy)-1,4-diaza-spiro[5.5]undecan-5-one hydrochloride und 12 g Triphenylphosphin werden in 450 ml Dioxan suspendiert. Anschließend werden 250ml Lösungsmittel abdestilliert und 6.45 g N-Chlorsuccinimid in 100 ml Acetonitril bei 41°C zugetropft. Die Reaktionsmischung wird zum Rückfluss erhitzt. Nach 100 min wird der Ansatz auf 29°C abgekühlt und 150 ml Methyltetrahydrofuran zugegeben. Der Niederschlag wird abfiltriert und dreimal mit je 50 ml Methyltetrahydrofuran gewaschen. Nach Trocknen bei 30°C erhält man 12 g eines dunkel gefärbten Feststoffs, der das Produkt als Hydrochlorid enthält, und der ohne Aufreinigung in der nächsten Stufe weiter umgesetzt wird.
Massenspektrum (ESI+): m/z = 377 [M+H]+ 10 g of (trans) -9- (4-hydroxy-7-methoxy-quinazolin-6-yloxy) -1,4-diaza-spiro [5.5] undecane-5-one hydrochloride and 12 g of triphenylphosphine are suspended in 450 ml of dioxane , Then, 250 ml of solvent are distilled off and 6.45 g of N-chlorosuccinimide in 100 ml of acetonitrile are added dropwise at 41 ° C. The reaction mixture is heated to reflux. After 100 minutes, the batch is cooled to 29 ° C and added to 150 ml of methyltetrahydrofuran. The precipitate is filtered off and washed three times with 50 ml of methyltetrahydrofuran. After drying at 30 ° C to obtain 12 g of a dark colored solid containing the product as the hydrochloride, and is further reacted without purification in the next stage.
Mass spectrum (ESI + ): m / z = 377 [M + H] +

Beispiel 12Example 12 (trans)-9-[4-(3-Chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one(Trans) -9- [4- (3-Chloro-2-fluoro-phenylamino) -7-methoxy-quinazolin-6-yloxy] -1,4-diaza-spiro [5.5] undecane-5-one

Figure imgb0040
Figure imgb0040

Verfahrensschritt OProcess step O

12g des unreinen (trans)-9-(4-Chloro-7-methoxy-quinazolin-6-yloxy)-1,4-diaza-spiro[5.5]undecan-5-one hydrochlorides aus vorheriger Stufe werden bei RT innerhalb von 90 min portionsweise zu einer Lösung von 3.9 g 3-Chlor-2-fluoranilin in 60 ml 2N Salzsäure gegeben. Die Suspension wird für 60 min auf 40°C erwärmt.12 g of the impure (trans) -9- (4-chloro-7-methoxy-quinazolin-6-yloxy) -1,4-diaza-spiro [5.5] undecane-5-one hydrochloride from the previous step are incubated at RT within 90 min added in portions to a solution of 3.9 g of 3-chloro-2-fluoroaniline in 60 ml of 2N hydrochloric acid. The suspension is heated to 40 ° C for 60 min.

Anschließend werden 60 ml Toluol zugegeben und der Ansatz auf RT abgekühlt. Nach 50 min wird filtriert und der Niederschlag mit 50 ml Toluol und 50ml ges. NaCl-Lösung gewaschen. Nach Trocknen bei 40°C erhält man 10 g eines Feststoffs, der das Produkt enthält. Das Produkt wird durch basische Chromatographie an Kieselgel aufgereinigt.
Massenspektrum (ESI+): m/z = 486 [M+H]+
1 H NMR (400 MHz, DMSO): 9,60 (1 H, s); 8,37 (1 H, s); 7,82 (1 H, s); 7,45-7,54 (2H, m), 7,36 (1 H, s); 7,28 (dt, 1 H); 7,22 (1 H, s); 4,63-4,67 (1 H, m); 3,95 (3H, s); 3,11-3,15 (2H, m); 2,82-2,86 (2H, m); 2,30 (1H, s); 2,13-2,22 (2H, m); 1,83-1,96 (4H, m); 1,44-1,51 (2H, m).Then 60 ml of toluene are added and the mixture is cooled to RT. After 50 min, filtered and the precipitate with 50 ml of toluene and 50ml sat. Washed NaCl solution. After drying at 40 ° C., 10 g of a solid containing the product are obtained. The product is purified by basic chromatography on silica gel.
Mass spectrum (ESI + ): m / z = 486 [M + H] +
1 H NMR (400 MHz, DMSO): 9.60 (1H, s); 8.37 (1H, s); 7.82 (1H, s); 7.45-7.54 (2H, m), 7.36 (1H, s); 7.28 (dt, 1H); 7.22 (1H, s); 4.63-4.67 (1H, m); 3.95 (3H, s); 3.11-3.15 (2H, m); 2.82-2.86 (2H, m); 2.30 (1H, s); 2,13-2,22 (2H, m); 1.83-1.96 (4H, m); 1.44-1.51 (2H, m).

Beispiel 13Example 13 (trans)-9-(3-Benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy)-5-oxo-1,4-diaza-spiro[5.5]undecane-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester(Trans) -9- (3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy) -5-oxo-1,4-diaza-spiro [5.5] undecane-1, 4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester

Figure imgb0041
Figure imgb0041

Verfahrensschritt PProcess step P

Zu einer Suspension aus 1.3 g 3-Benzyl-6-hydroxy-7-methoxy-3H-quinazolin-4-one, 2g (cis)-9-Hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecane-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester und 1.8 g Triphenylphosphin in 10 ml N-Methyl-2-pyrrolidon werden 1.36 ml Azo-dicarbonsäure-diisopropylester innerhalb von 90 min zugetropft. Der Ansatz wird für 4 h gerührt. Der Ansatz, der das Produkt enthält, wird direkt in der nächsten Stufe weiterverwendet.
Massenspektrum (ESI+): m/z = 683 [M+H]+ To a suspension of 1.3 g of 3-benzyl-6-hydroxy-7-methoxy-3H-quinazolin-4-one, 2g (cis) -9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane 1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester and 1.8 g of triphenylphosphine in 10 ml of N-methyl-2-pyrrolidone are added dropwise 1.36 ml of diisopropyl azobisic acid within 90 min. The batch is stirred for 4 h. The batch containing the product will continue to be used directly in the next stage.
Mass spectrum (ESI + ): m / z = 683 [M + H] +

Beispiel 14Example 14 (trans)-9-(3-Benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy)-5-oxo-1,4-diaza-spiro[5.5]undecane-1-carboxylic acid benzyl ester(Trans) -9- (3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy) -5-oxo-1,4-diaza-spiro [5.5] undecane-1- carboxylic acid benzyl ester

Figure imgb0042
Figure imgb0042

Verfahrensschritt QProcess step Q

Zum Ansatz aus vorheriger Stufe, der den (trans)-9-(3-Benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy)-5-oxo-1,4-diaza-spiro[5.5]undecane-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester enthält, werden 2.5 ml 4 M HCl in Dioxan zugegeben. Nach 19 h werden 2 ml 4 M HCl in Dioxan zugegeben und der Ansatz auf 40°C erwärmt. Nach 3 h wird die Temperatur auf 60°C erhöht, der Ansatz mit 60 ml Dioxan verdünnt und 10 ml 4 M HCl in Dioxan zugegeben. Nach 16 h wird der Ansatz im Vakuum eingeengt und der Rückstand in 50 ml Dichlormethan aufgenommen. Nach dreimaligem Waschen mit jeweils 50 ml Wasser wird die organische Phase eingedampft. Der Rückstand wird chromatographisch an Kieselgel aufgereinigt. Die entsprechenden Fraktionen werden eingedampft und der Rückstand mit 150 ml Ethylacetat ausgekocht. Nach Isolation und Trocknen des Niederschlags erhält man 2.1 g Produkt.
Massenspektrum (ESI+): m/z = 583 [M+H]+ To the approach from the previous stage, which the (trans) -9- (3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy) -5-oxo-1,4-diaza- spiro [5.5] undecane-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester, 2.5 ml of 4 M HCl in dioxane are added. After 19 h, 2 ml of 4 M HCl in dioxane are added and the batch is heated to 40.degree. After 3 h, the temperature is raised to 60 ° C, the batch diluted with 60 ml of dioxane and 10 ml of 4 M HCl in dioxane was added. After 16 h, the mixture is concentrated in vacuo and the residue taken up in 50 ml of dichloromethane. After washing three times with 50 ml of water each time, the organic phase is evaporated. The residue is purified by chromatography on silica gel. The appropriate fractions are evaporated and the residue is boiled with 150 ml of ethyl acetate. After isolation and drying of the precipitate, 2.1 g of product are obtained.
Mass spectrum (ESI + ): m / z = 583 [M + H] +

Beispiel 15Example 15 (cis)-9-(3-Benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy)-5-oxo-1,4-diaza-spiro[5.5]undecane-1-carboxylic acid benzyl ester(Cis) -9- (3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy) -5-oxo-1,4-diaza-spiro [5.5] undecane-1- carboxylic acid benzyl ester

Figure imgb0043
Figure imgb0043

Verfahrensschritt RProcess step R

Zu einer Mischung aus 2 g 3-Benzyl-6-hydroxy-7-methoxy-3H-quinazolin-4-one, 2.37g (trans)-9-Hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecane-1-carboxylic acid benzyl ester und 2.79 g Triphenylphosphin in 20 ml N-Methyl-2-pyrrolidon werden unter Kühlung 2.1 ml Azo-dicarbonsäure-diisopropylester zugetropft. Nach 20 min werden 20 ml N-Methyl-2-pyrrolidon zugefügt und der Ansatz wird für 4 h gerührt. Der Niederschlag wird bei 0°C abgesaugt und mit 50 ml Methyl-tert-butylether gewaschen. Nach Trocken erhält man 3.3g Produkt, das noch N-Methyl-2-pyrrolidon enthält.
Massenspektrum (ESI+): m/z = 583 [M+H]+ To a mixture of 2 g of 3-benzyl-6-hydroxy-7-methoxy-3H-quinazolin-4-one, 2.37 g of (trans) -9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane-1-carboxylic acid benzyl ester and 2.79 g of triphenylphosphine in 20 ml of N-methyl-2-pyrrolidone are added dropwise 2.1 ml of azo-dicarboxylic acid diisopropyl ester with cooling. After 20 minutes, 20 ml of N-methyl-2-pyrrolidone are added and the reaction is stirred for 4 h. The precipitate is filtered off with suction at 0 ° C. and washed with 50 ml of methyl tert-butyl ether. Dry gives 3.3 g of product which still contains N-methyl-2-pyrrolidone.
Mass spectrum (ESI + ): m / z = 583 [M + H] +

Beispiel 16Example 16 (cis)-9-(4-Hydroxy-7-methoxy-quinazolin-6-yloxy)-1,4-diaza-spiro[5.5]undecan-5-one(Cis) -9- (4-hydroxy-7-methoxy-quinazolin-6-yloxy) -1,4-diaza-spiro [5.5] undecane-5-one

Figure imgb0044
Figure imgb0044

Verfahrensschritt SProcess step S

Zu einer Mischung aus 1.7 g (cis)-9-(3-Benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy)-5-oxo-1,4-diaza-spiro[5.5]undecane-1-carboxylic acid benzyl ester in 30 ml Ethanol und 10 ml 1 M Salzsäure werden 300 mg Palladium (10%) auf Kohle zugefügt. Nach 25 h Hydrieren bei 80°C wird filtriert und die Lösung zur Trockne eingedampft, wobei 1.4g Rohprodukt anfallen. Das Rohprodukt wird mit 100 ml Ethanol ausgekocht und nach Filtration wird das Filtrat eingeengt. Der Rückstand wird in 50 ml Acetonitril suspendiert und nach Zugabe von 1 g Kaliumcarbonat für 23 h gerührt. Der Ansatz wird eingeengt und nach Zugabe von 20 ml Dichlormethan und 4 ml Methanol chromatographisch an Kieselgel aufgereinigt. 500 mg Produkt werden erhalten.
Massenspektrum (ESI+): m/z = 359 [M+H]+ To a mixture of 1.7 g of (cis) -9- (3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy) -5-oxo-1,4-diaza-spiro [ 5.5] undecane-1-carboxylic acid benzyl ester in 30 ml of ethanol and 10 ml of 1 M hydrochloric acid are added to 300 mg of palladium (10%) on carbon. After 25 h hydrogenation at 80 ° C is filtered and the solution evaporated to dryness, resulting in 1.4 g of crude product. The crude product is 100 Of ethanol boiled and after filtration, the filtrate is concentrated. The residue is suspended in 50 ml of acetonitrile and, after addition of 1 g of potassium carbonate, stirred for 23 h. The mixture is concentrated and, after addition of 20 ml of dichloromethane and 4 ml of methanol, purified by chromatography on silica gel. 500 mg of product are obtained.
Mass spectrum (ESI + ): m / z = 359 [M + H] +

Beispiel 17Example 17 (cis)-9-[4-(3-Chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one(Cis) -9- [4- (3-Chloro-2-fluoro-phenylamino) -7-methoxy-quinazolin-6-yloxy] -1,4-diaza-spiro [5.5] undecane-5-one

Figure imgb0045
Figure imgb0045

Verfahrensschritt TProcess step T

Zu einer Mischung von 100 mg 7-Methoxy-6-(5-oxo-1,4-diaza-spiro[5.5]undec-9-yloxy)-3H-quinazolin-4-one und 0.23 ml Triethylamin in 5 ml Acetonitril werden 0.13 ml Phosphoroxytrichlorid zugefügt. Nach 1 h werden 0.04 ml 3-Chlor-2-Fluoranilin zugegeben. Nach 18 h wird 1 ml Wasser zugefügt und die das Gemisch bis auf 2 ml Volumen eingeengt. Nach Aufreinigung mittels präparativer HPLC erhält man 95 mg Produkt.
Massenspektrum (ESI+): m/z = 486 [M+H]+
1 H NMR (400 MHz, DMSO): 9,58 (1 H, s); 8,36 (1 H, s); 7,81 (1 H, s); 7,54 (1 H, t); 7,49 (1 H, t); 7,42 (1 H, s); 7,29 (1 H, t), 7,20 (1 H, s); 4,49-4,58 (1 H, m); 3,93 (3H, s); 3,11-3,15 (2H, m); 2,80-2,85 (2H, m); 2,38 (1 H, s); 1,88-2,02 (4H, m); 1,69-1,81 (4H, m).To a mixture of 100 mg of 7-methoxy-6- (5-oxo-1,4-diaza-spiro [5.5] undec-9-yloxy) -3H-quinazolin-4-one and 0.23 ml of triethylamine in 5 ml of acetonitrile 0.13 ml of phosphorus oxytrichloride added. After 1 h, 0.04 ml of 3-chloro-2-fluoroaniline are added. After 18 h, 1 ml of water is added and the mixture is concentrated to 2 ml volume. Purification by preparative HPLC gives 95 mg of product.
Mass spectrum (ESI + ): m / z = 486 [M + H] +
1 H NMR (400 MHz, DMSO): 9.58 (1H, s); 8.36 (1H, s); 7.81 (1H, s); 7.54 (1H, t); 7.49 (1H, t); 7.42 (1H, s); 7.29 (1H, t), 7.20 (1H, s); 4.49-4.58 (1H, m); 3.93 (3H, s); 3.11-3.15 (2H, m); 2.80-2.85 (2H, m); 2.38 (1H, s); 1.88-2.02 (4H, m); 1.69-1.81 (4H, m).

Beispiel 18Example 18 (trans)-9-Hydroxy-1,4-diaza-spiro[5.5]undecan-5-one hydrochloride (cis)-9-Hydroxy-1,4-diaza-spiro[5.5]undecan-5-one hydrochloride(trans) -9-hydroxy-1,4-diaza-spiro [5.5] undecane-5-one hydrochloride (cis) -9-hydroxy-1,4-diaza-spiro [5.5] undecane-5-one hydrochloride

Figure imgb0046
Figure imgb0046

Verfahrensschritt UProcess step U

Zu einer Mischung aus 500 mg 1,4-Diaza-spiro[5.5]undecane-5,9-dione hydrochloride in 5 ml Wasser werden 50 mg Platindioxid zugefügt. Nach 3 h Hydrieren wird filtriert und die Lösung zur Trockne eingedampft. Es wird zweimal mit je 50 ml n-Propanol nachgedampft und zurück bleiben 500mg eines trans-/cis-Gemisches von 9-Hydroxy-1,4-diaza-spiro[5.5]undecan-5-one hydrochloride.
Massenspektrum (ESI+): m/z = 185 [M+H]+ To a mixture of 500 mg of 1,4-diaza-spiro [5.5] undecane-5,9-dione hydrochloride in 5 ml of water is added 50 mg of platinum dioxide. After hydrogenation for 3 h, it is filtered and the solution is evaporated to dryness. It is post-evaporated twice with 50 ml of n-propanol and leave 500 mg of a trans / cis mixture of 9-hydroxy-1,4-diaza-spiro [5.5] undecane-5-one hydrochloride.
Mass spectrum (ESI + ): m / z = 185 [M + H] +

Beispiel 19Example 19 5,9-Dioxo-1,4-diaza-spiro[5.5]undecane-1-carboxylic acid benzyl ester5,9-Dioxo-1,4-diaza-spiro [5.5] undecane-1-carboxylic acid benzyl ester

Figure imgb0047
Figure imgb0047

Verfahrensschritt VProcess step V

Zu einer Mischung aus 20g 1,4-Diaza-spiro[5.5]undecane-5,9-dione hydrochloride in 100 ml Tetrahydrofuran und 82 ml 50%iger Kaliumcarbonatlösung werden unter Kühlung 14.4 ml Chlorameisensäurebenzylester zugegeben. Nach 2.5 h werden 250 ml Wasser zugefügt und der Niederschlag abfiltriert. Nach Waschen mit 200 ml Wasser und 200 ml Methyl-tert-butylether und Trocknen erhält man 24.3 g Produkt.
Massenspektrum (ESI+): m/z = 317 [M+H]+ 14.4 ml of benzyl chloroformate are added with cooling to a mixture of 20 g of 1,4-diaza-spiro [5.5] undecane-5,9-dione hydrochloride in 100 ml of tetrahydrofuran and 82 ml of 50% potassium carbonate solution. After 2.5 h, 250 ml of water are added and the precipitate is filtered off. After washing with 200 ml of water and 200 ml of methyl tert-butyl ether and drying to obtain 24.3 g of product.
Mass spectrum (ESI + ): m / z = 317 [M + H] +

Beispiel 20Example 20 (trans)-9-Hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecane-1-carboxylic acid benzyl ester(trans) -9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane-1-carboxylic acid benzyl ester

Figure imgb0048
Figure imgb0048

Verfahrensschritt WProcess step W

Zu einer Mischung aus 5 g 1,4-Diaza-spiro[5.5]undecane-5,9-dione hydrochloride in 20 ml Wasser werden 50 mg Platindioxid zugefügt. Nach 22 h Hydrieren werden 25 mg Platindioxid zugefügt. Nach 26 h Hydrieren wird filtriert und das Filtrat mit 35 g Kaliumcarbonat und 25 ml Tetrahydrofuran versetzt. 3.43 ml Chlorameisensäurebenzylester werden zugegeben und der Ansatz für 6 d gerührt. 25 g Kaliumcarbonat werden zugegeben und der Ansatz für 4 d gerührt. 3.5 ml Chlorameisensäurebenzylester werden zugegeben. Nach 20 h werden 200 ml Wasser zugefügt und nach 1 h nachrühren wird der Niederschlag abgesaugt und mit 100 ml Methyl-tert-butylether gewaschen. Man erhält 3.4 g Feststoff, der hauptsächlich aus dem Produkt besteht.
Massenspektrum (ESI+): m/z = 319 [M+H]+ To a mixture of 5 g of 1,4-diaza-spiro [5.5] undecane-5,9-dione hydrochloride in 20 ml of water are added 50 mg of platinum dioxide. After hydrogenation for 22 h, 25 mg of platinum dioxide are added. After hydrogenation for 26 h, it is filtered and the filtrate is mixed with 35 g of potassium carbonate and 25 ml of tetrahydrofuran. 3.43 ml of benzyl chloroformate are added and the batch is stirred for 6 d. 25 g of potassium carbonate are added and the batch is stirred for 4 d. 3.5 ml of benzyl chloroformate are added. After 20 h, 200 ml of water are added and after stirring for 1 h, the precipitate is filtered off with suction and washed with 100 ml of methyl tert-butyl ether. This gives 3.4 g of solid, which consists mainly of the product.
Mass spectrum (ESI + ): m / z = 319 [M + H] +

Verfahrensschritt XProcess step X

Zu 20 g 5,9-Dioxo-1,4-diaza-spiro[5.5]undecane-1-carboxylic acid benzyl ester in 100 ml Tetrahydrofuran, 100 ml Ethanol, 80 ml Wasser und 20 ml 0.1 N Natronlauge werden 7.2 g Natriumborhydrid gegeben. Nach 16.5 h Rühren bei RT und 1 h bei 60°C werden unter Eiskühlung 80 ml 2M Salzsäure und 200 ml Wasser zugetropft. Nach 2 h wird der Niederschlag abgesaugt und mit 200 ml Wasser gewaschen. Nach Trocknen des Niederschlags und Chromatographische Reinigung an Kieselgel werden 8 g Produkt isoliert.
Massenspektrum (ESI+): m/z = 319 [M+H]+ To 20 g of 5,9-dioxo-1,4-diaza-spiro [5.5] undecane-1-carboxylic acid benzyl ester in 100 ml of tetrahydrofuran, 100 ml of ethanol, 80 ml of water and 20 ml of 0.1 N sodium hydroxide solution are added 7.2 g of sodium borohydride , After 16.5 h stirring at RT and 1 h at 60 ° C 80 ml of 2M hydrochloric acid and 200 ml of water are added dropwise with ice cooling. After 2 h, the precipitate is filtered off with suction and washed with 200 ml of water. After drying the precipitate and chromatographic purification on silica gel, 8 g of product are isolated.
Mass spectrum (ESI + ): m / z = 319 [M + H] +

Beispiel 21Example 21 (trans)-9-Hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecane-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester(trans) -9-Hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester

Figure imgb0049
Figure imgb0049

Verfahrensschritt YProcess step Y

Eine Mischung aus 200 mg (trans)-9-Hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecane-1-carboxylic acid benzyl ester, 87 mg Kaliumcarbonat, 274 mg Di-tert-butyldicarbonat und 76 mg 4-(Dimethylamino)-pyridin in 5 ml Acetonitril werden für 2 h bei RT gerührt. Das Gemisch wird durch präparative HPLC aufgereinigt und man erhält 100 mg Produkt.
Massenspektrum (ESI+): m/z = 419 [M+H]+ A mixture of 200 mg of (trans) -9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane-1-carboxylic acid benzyl ester, 87 mg of potassium carbonate, 274 mg of di-tert-butyl dicarbonate and 76 mg 4- (Dimethylamino) -pyridine in 5 ml of acetonitrile are stirred for 2 h at RT. The mixture is purified by preparative HPLC to give 100 mg of product.
Mass spectrum (ESI + ): m / z = 419 [M + H] +

Beispiel 22Example 22 (cis)-9-Hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecane-1-carboxylic acid benzyl ester(cis) -9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane-1-carboxylic acid benzyl ester

Figure imgb0050
Figure imgb0050

Verfahrensschritt ZProcess step Z

Zu einer Lösung von 75 g ,4-Diaza-spiro[5.5]undecane-5,9-dione hydrochoride in 350 ml 1 M Natronlauge werden bei RT portionsweise 14.3 g Natriumborhydrid gegeben. Nach 35 min werden unter Kühlung innerhalb von 30 min 60 ml konz. Salzsäure zugetropft. Es werden 390 g Kaliumcarbonat zugefügt. Nach Zugabe von 300 ml Tetrahydrofuran und 67 ml Chlorameisensäurebenzylester wird der Ansatz für 1.5 h auf 48°C erhitzt. Es werden 900 ml Methyl-tert-butylether zugegeben und nach abkühlen auf 22°C 1.6 l Wasser zugefügt. Nach 1 h Rühren wird die Suspension abgesaugt und der Filterkuchen mit 500 ml Wasser und 1 I Methyl-tert-butylether gewaschen. Nach Trocknen des Filterkuchens erhält man 77 g Produkt, das hauptsächlich aus dem cis-Isomer besteht.
Massenspektrum (ESI+): m/z = 319 [M+H]+ To a solution of 75 g of 4-diaza-spiro [5.5] undecane-5,9-dione hydrochoride in 350 ml of 1 M sodium hydroxide solution at RT 14.3 g of sodium borohydride are added in portions. After 35 min, with cooling within 30 min 60 ml of conc. hydrochloric acid dropwise. 390 g of potassium carbonate are added. After addition of 300 ml of tetrahydrofuran and 67 ml of benzyl chloroformate, the mixture is heated to 48 ° C. for 1.5 h. 900 ml of methyl tert-butyl ether are added and, after cooling to 22 ° C., 1.6 l of water are added. After stirring for 1 h, the suspension is filtered off with suction and the filter cake is washed with 500 ml of water and 1 l of methyl tert-butyl ether. After drying the filter cake to obtain 77 g of product, which consists mainly of the cis isomer.
Mass spectrum (ESI + ): m / z = 319 [M + H] +

Beispiel 23Example 23 (cis)-1-(2-tert-Butoxycarbonylamino-ethylamino)-4-hydroxy-cyclohexanecarboxylic acid methyl ester(cis) -1- (2-tert-Butoxycarbonylamino-ethylamino) -4-hydroxycyclohexanecarboxylic acid methyl ester

Figure imgb0051
Figure imgb0051

Verfahrensschritt ZZProcess step ZZ

Zu einer Lösung aus 500 mg 5,9-Dioxo-1,4-diaza-spiro[5.5]undecane-4-carboxylic acid tert-butyl ester in 5 ml Methanol werden 16.7 mg Natriumborhydrid zugefügt. Nach 4 h wird der Ansatz eingedampft und mit Tetrahydrofuran nachgedampft. Der Rückstand enthält das Produkt.
Massenspektrum (ESI+): m/z = 317 [M+H]+ To a solution of 500 mg of 5,9-dioxo-1,4-diaza-spiro [5.5] undecane-4-carboxylic acid tert-butyl ester in 5 ml of methanol is added 16.7 mg of sodium borohydride. After 4 h, the mixture is evaporated and evaporated with tetrahydrofuran. The residue contains the product.
Mass spectrum (ESI + ): m / z = 317 [M + H] +

Beispiel 24Example 24 (cis)-[2-(4-Hydroxy-1-hydroxymethyl-cyclohexylamino)-ethyl]-carbamic acid tert-butyl ester(Cis) - [2- (4-Hydroxy-1-hydroxymethyl-cyclohexylamino) -ethyl] -carbamic acid tert-butyl ester

Figure imgb0052
Figure imgb0052

Verfahrensschritt ZZZProcess step ZZZ

Zu einer Mischung aus 1 g 5,9-Dioxo-1,4-diaza-spiro[5.5]undecane-4-carboxylic acid tert-butyl ester in 10 ml 1 M Kaliumcarbonatlösung werden unter Kühlung 161 mg Natriumborhydrid zugefügt. Nach 14.5 h bei 50°C werden 10 ml Ethylacetat zugegeben und nach Phasentrennung die organische Phase eingeengt. Nach chromatographischer Aufreinigung des Rückstands an Kieselgel werden 580 mg eines Gemisches isoliert, das das Produkt enthält.
Massenspektrum (ESI+): m/z = 289 [M+H]+ To a mixture of 1 g of 5,9-dioxo-1,4-diaza-spiro [5.5] undecane-4-carboxylic acid tert-butyl ester in 10 ml of 1 M potassium carbonate solution 161 mg of sodium borohydride are added with cooling. After 14.5 h at 50 ° C, 10 ml of ethyl acetate are added and the organic phase is concentrated by phase separation. After chromatographic purification of the residue on silica gel, 580 mg of a mixture containing the product are isolated.
Mass spectrum (ESI + ): m / z = 289 [M + H] +

Claims (11)

  1. Process for the stereoselective preparation of the compound of formula (1A)
    Figure imgb0079
     optionally in the form of the tautomers thereof, and optionally the pharmacologically acceptable acid addition salts thereof,
    characterised in that the process comprises reaction steps (A), (B), (V), (X), (R), (S) and (T), wherein
    (A) denotes the reaction of 1,4-cyclohexanedione-mono-ethyleneketal to form a compound of formula (1)
    Figure imgb0080
    (B) denotes the reaction of a compound of formula (1) to form the compound of formula (2)
    Figure imgb0081
    (V) denotes the reaction of a compound of formula (2) with a protective group reagent to form the compound of formula (19)
    Figure imgb0082
    (X) denotes the reaction of a compound of formula (19) to form the compound of formula (18)
    Figure imgb0083
    (R) denotes the reaction of a compound of formula (18) with a compound of formula (23)
    Figure imgb0084
     to form a compound of formula (21)
    Figure imgb0085
    (S) denotes the cleavage of the protective groups from the compound of formula (21) to form a compound of formula (22)
    Figure imgb0086
     and
    (T) denotes the chlorination of the compound of formula (22) and subsequent reaction with 3-chloro-2-fluoroaniline,
    wherein steps (A) to (T) take place successively in the order stated and the protective group Sg1 may represent a group selected from among optionally substituted benzyl, Cbz and optionally substituted acetyl, the protective group Sg2 may represent optionally substituted benzyl.
  2. Process for the stereoselective preparation of a compound of formula (18), characterised in that the process consists of process steps (A), (B), (V) and (X) according to claim 1.
  3. Process for the stereoselective preparation of the compound of formula (1B)
    Figure imgb0087
     optionally in the form of the tautomers thereof, and optionally the pharmacologically acceptable acid addition salts thereof, characterised in that the process comprises reaction steps (A), (B), (Z), (H), (P), (Q), (M), (N) and (O), wherein
    (A) denotes the reaction of 1,4-cyclohexanedione-mono-ethyleneketal to form a compound of formula (1)
    Figure imgb0088
    (B) denotes the reaction of a compound of formula (1) to form the compound of formula (2)
    Figure imgb0089
    (Z) denotes the reaction of a compound of formula (2) to form the compound of formula (16)
    Figure imgb0090
    (H) denotes the reaction of a compound of formula (16) to form the compound of formula (6)
    Figure imgb0091
    (P) denotes the reaction of a compound of formula (6) with a compound of formula (23)
    Figure imgb0092
     to form a compound of formula (7)
    Figure imgb0093
    (Q +M) denotes the cleavage of the protective groups from the compound of formula (7) to form a compound of formula (12)
    Figure imgb0094
     and
    (N + O) denotes the chlorination of the compound of formula (12) and subsequent reaction with 3-chloro-2-fluoroaniline,
    wherein steps (A) to (O) take place successively in the order stated and the protective group Sg1 may represent a group selected from among optionally substituted benzyl, Cbz and optionally substituted acetyl,
    the protective group Sg2 may represent optionally substituted benzyl, the protective group Sg3 may be selected from among Boc and allyloxycarbonyl.
  4. Process for the stereoselective preparation of a compound of formula (1 B), characterised in that in the process according to claim 3 the process steps [(Z), (H)] are replaced by the process steps [(C ), (D), (E) or (F), and (G)], wherein
    (C) denotes the reaction of a compound of formula (2) to form the compound of formula (3)
    Figure imgb0095
    (D) denotes the reaction of a compound of formula (3) to form the compound of formula (4)
    Figure imgb0096
    (E) or (F) denotes the reaction of a compound of formula (4) to form the compound of formula (5)
    Figure imgb0097
     wherein in step (F) the compound (5) is not isolated,
    and
    (G) denotes the reaction of a compound of formula (5) to form the compound of formula (6)
    Figure imgb0098
    wherein steps (C) to (G) take place successively in the order stated and the protective group Sg1 may represent a group selected from among optionally substituted benzyl, Cbz and optionally substituted acetyl, the protective group Sg3 may represent a group selected from among Boc and allyloxycarbonyl.
  5. Process for the stereoselective preparation of a compound of formula (1 B), characterised in that in the process according to claim 3 the process steps [(P), (Q), (M)] are replaced by the process steps [(I), (J), (K), (L)],
    wherein
    (I) denotes the reaction of a compound of formula (6) with a compound of formula (15)
    Figure imgb0099
     to form the compound of formula (9)
    Figure imgb0100
    (J + K) denotes the cleavage of the protective groups and hydrogenolytic reduction of a compound of formula (9) to form the compound of formula (11)
    Figure imgb0101
     and
    (L) denotes the reaction of a compound of formula (11) to form the compound of formula (12)
    Figure imgb0102
    wherein steps (I) to (L) take place successively in the order stated and the protective group Sg1 may represent a group selected from among optionally substituted benzyl, Cbz and optionally substituted acetyl, the protective group Sg3 may represent a group selected from among Boc and allyloxycarbonyl.
  6. Compound of formula (22) as defined in claim 1, as well as the physiologically acceptable salts thereof with inorganic or organic acids and bases.
  7. Compound of formula (13),
    Figure imgb0103
     as well as the physiologically acceptable salts thereof with inorganic or organic acids and bases.
  8. Compound of formula (4) as defined in claim 4, as well as the physiologically acceptable salts thereof with inorganic or organic acids and bases.
  9. Compound of formula (5) as defined in claim 4, as well as the physiologically acceptable salts thereof with inorganic or organic acids and bases.
  10. Compound of formula (6) as defined in claim 4.
  11. Compound of formula (12) as defined in claim 3, as well as the physiologically acceptable salts thereof with inorganic or organic acids and bases.
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